The Marriage of Small Molecules and Biologics

Approaches in using small-molecule and peptide synthesis offer promise in widening the scope of drug candidates.
May 02, 2011
Volume 35, Issue 5

The ongoing task of drug development is to move promising discovery candidates into commercial production. Different modalities of small-molecule or biologic-based drugs offer relative advantages and disadvantages in achieving these goals. Recent efforts in drug development seek to marry the best of both modalities with specialized approaches, such as stapled peptides and other improvements in peptide synthesis.

Stapled peptides

Patricia Van Arnum
Stapled peptides use peptide-stabilization technology to enhance potency and cell permeability of a drug. Although the concept of stapled peptides is not new, stapled peptides as a field came into greater prominence last year when Roche signed a drug-development deal worth up to $1.1 billion with the biopharmaceutical company Aileron Therapeutics to discover, develop, and commercialize stapled peptides. Under the agreement, which was announced in August 2010, Roche is guaranteeing at least $25 million in funding for technology-access fees and continued research and development efforts by Aileron. The company is eligible to receive up to $1.1 billion in payments based on discovery, development, regulatory, and commercialization milestones if drug candidates are developed for five undisclosed drug targets in the following areas: oncology, virology, inflammation, metabolism, and central nervous system.

Stapled peptides are designed to address pharmacological limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules are able to penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule modulators ineffective. Although peptides and proteins have the size and functionality to effectively modulate intracellular protein–protein interactions, they often do not permeate cells and therefore are used to modulate extracellular targets such as receptors (1). These limitations of small molecules and existing biologics make a vast array of potential drug targets "undruggable." Approximately 80% of potential drug targets are considered "undruggable" by either modality (1, 2).

Peptides face certain limitations as drugs. They lack the ability to enter cells, are inherently unstable within the body, are rapidly broken down into inactive fragments by circulating enzymes, such as proteases, and are quickly filtered from the bloodstream by the kidneys. Stapled peptides seek to resolve those problems. Because many "undruggable" therapeutic targets include those protein–protein interactions in which a-helices are required in lock-and-key-type mechanisms, an approach is to design a-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target, and modulate the biological pathway (1).

Aileron stabilizes peptides by "stapling" them with hydrocarbon bonds into an a-helix. Once constrained in the a-helix structure, the peptides are protected from degradation by proteases. The stabilized a-helical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2).

Aileron was cofounded in 2005 by Gregory L. Verdine, chair of Aileron's scientific advisory board, professor of chemistry at Harvard University, director of the Harvard/Dana–Farber Program in Cancer Chemical Biology, and executive director of the Chemical Biology Initiative at the Dana–Farber Cancer Institute. In 2006, Aileron acquired exclusive rights from Harvard University and the Dana–Farber Cancer Institute to develop and commercialize a drug-discovery pipeline of stapled peptides. In 2006–2007, Aileron licensed rights from the fine-chemicals and technology firm Materia for catalysts used in olefin metathesis. Materia holds the rights to the olefin metathesis technology developed by Robert H. Grubbs, professor at the California Institute of Technology, who was awarded the Nobel Prize in Chemistry in 2005 with Richard R. Schrock and Yves Chauvin for their work in olefin metathesis using ruthenium-based catalysts. Part of the reaction scope of olefin metathesis is ring-closing metathesis (RCM), which transforms a diene into a cyclic alkene and is used to create macrocycles, including bioactive cyclic peptidomimetics. Grubbs was one of the first to offer research describing RCM to tether residues of helical peptides (3, 4).

lorem ipsum